Quality of life following adult veno-venous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review

Acute respiratory distress syndrome (ARDS) is a frequent cause of respiratory failure in critical care patients. It is defined by the acute onset of non-cardiogenic pulmonary edema and hypoxemia, which might require mechanical ventilation [1]. While the ARDS incidence covers 10% of all ICU admissions, 25% of these patients have severe ARDS leading to profound hypoxemia [2]. There are limited therapeutic options for ARDS patients [3, 4], mainly based on conventional mechanical ventilation and supportive care. Despite recent technological advances in ventilatory support, mortality rates remain high in this patient population (27–45%) [5].

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) has been successfully employed in adult patients with severe ARDS refractory to conventional ventilatory support [6, 7]. The use of ECMO as an adjunct to lung-protective ventilation strategies has been suggested to ameliorate ventilator-induced and ventilator-associated lung injury [8]. The Extracorporeal Life Support Organization (ELSO) registry showed that the number of adults treated with VV-ECMO doubled during the H1N1 global pandemic from 200 cases in 2008 to 495 cases in 2009 [9]. Moreover, ECMO has also been applied in severe respiratory compromised patients suffering from the on-going global coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [10, 11]. While still little is known on the true efficacy of ECMO in the COVID-19 setting, the natural resemblance of COVID-19 and seasonal influenza’s complications with respect to acute onset and symptoms prompt to ECMO implantation in most severe pulmonary decompensated patients [12, 13]. Despite the increased VV-ECMO application in the last decade, survival rates barely improved, with a current survival rate ranging from 56 to 64% [14]. Besides clinical endpoints such as survival and survival time, only a few studies to date focused on outcomes in terms of quality of life in patients receiving VV-ECMO for ARDS.

Health-related quality of life (HRQoL) is a multidimensional construct that describes the perceived impact of health status, including physical, psychological, and social domains of health [15]. The results from a former review on adult VV-ECMO survivors indicate varying degrees of a reduced HRQoL [16]. Moreover, there is evidence that ARDS survivors may experience physical impairment and psychiatric symptoms following ICU discharge [17‐19]. Zwischenberger and Pitcher stated that patients often require thorough assistance and rehabilitation, including physical, occupational, nutritional, and speech therapy after successful weaning from ECMO support [20]. The cognitive, psychiatric, and physical impairments have shown to recover between 6 and 12 months following ICU discharge [21], while in some cases, physical issues can prevail for over 3 years [22]. These morbidities contribute to a significant reduction in HRQoL following ECMO. To date, merely a few studies focused on the HRQoL in ARDS patients treated with VV-ECMO [23, 24] and the majority of the available studies did not discriminate between VV-ECMO and veno-arterial ECMO (VA-ECMO) patients [25‐27]. While VV-ECMO provides solely pulmonary support, the VA-ECMO configuration provides both cardiac and pulmonary support, these parameters affect the indication and possibly the HRQoL following therapy [22]. Notably, the median duration of VA-ECMO support is shorter (median of 4 days) [28] compared to VV-ECMO support (median of 10 days) [29]. For these reasons, HRQoL may show different outcomes in VA-ECMO and VV-ECMO survivors. Given the increase of VV-ECMO applications to support refractory gas exchange in ARDS patients [30] and specifically, COVID-19 ARDS-related patients, a better understanding of HRQoL in these patients is warranted.

Despite the increasing number of reports describing the HRQoL of patients treated with ECMO, a study focusing specifically on HRQoL in ARDS patients supported by VV-ECMO is still lacking. Additionally, actual HRQoL scores are not always described or displayed in previous studies, which makes interpretation of the effect of VV-ECMO therapy on HRQoL in ARDS-related patients challenging. The present systematic review aims to describe HRQoL and long-term outcomes in adult ARDS patients supported by VV-ECMO.

Given the increased use of VV-ECMO to support refractory gas exchange in ARDS patients, efforts should be devoted to gain a better understanding of the HRQoL in ECMO survivors to ultimately improve patient care following ECMO support. While earlier systematic reviews lack focus specifically on the HRQoL of ARDS patients supported by VV-ECMO, the current review assessed the HRQoL of adult VV-ECMO survivors, indicating a lower HRQoL in these patients compared to the general healthy population.

Eight studies were included in this review, which revealed that VV-ECMO survivors have lower SF-36 scores, i.e., reduced physical, mental, and social dimension scores compared to the general healthy population norms. This is consistent with previous studies showing reduced SF-36 scores in most SF-36 domains [24, 47]. Nevertheless, these results should be interpreted with caution, as they may be attributable to other factors than treatment using VV-ECMO by itself, for example, the length of hospital stay or severity of the underlying disease [48]. Although some information regarding the HRQoL in ECMO survivors is available, data revealing the VV-ECMO survivors’ experience related to their health problems occurring after discharge from the hospital remains scarce. To explore the problems and health needs of patients who had been successfully weaned from VV-ECMO, a qualitative study is necessary to provide a better understanding of the patient’s experiences [49, 50]. Insight into the patient’s health needs and physical, psychological, and social problems that occur after discharge from the hospital will contribute to the initiation of additional treatment modalities. Previous studies emphasize the importance of qualitative studies to provide an invaluable perspective of the patients’ needs across all quality of life domains [51, 52].

Notably, as compared to patients supported conventionally, selected studies suggested no reduction of HRQoL for VV-ECMO survivors [40, 43, 45, 46]. One study reported a better HRQoL in VV-ECMO survivors [40]. In contrast, three others reported similar HRQoL across the two groups—although patients treated with VV-ECMO had more severe underlying pathology compared to those treated conventionally [43, 45, 46]. Wang and colleagues argued that the difference in respiratory support mode might explain the comparable HRQoL between VV-ECMO and conventionally treated survivors. The ventilatory strategies used in VV-ECMO patients might have offered better protection against lung injury resulting in improved long-term outcomes [46].

Similarly, Peek et al. suggested that the comparable HRQoL outcomes between both groups might result from the fact that VV-ECMO protects the pulmonary system from high pressure and FiO₂ ventilation, allowing a minimum iatrogenic contribution to lung injury [43]. Additionally, the clinics included in this study were highly experienced centers; hence, optimal outcomes were to be expected [43]. On the other hand, Grasselli et al. reported improved HRQoL, as shown by a lower median reduction of SF-36 scores in VV-ECMO survivors compared to their non-ECMO counterparts [40]. The authors did not find a clear explanation of why VV-ECMO survivors showed better long-term outcomes in just the general health domain. They hypothesized that an improved HRQoL in VV-ECMO survivors might be attributable to ultra-protective ventilation during ECMO support, which may have reduced the risk of polyneuropathy and myopathies associated with mechanical ventilation [40]. This may explain the improved outcome in VV-ECMO patients, despite a longer mechanical ventilation duration in this population. Additionally, advanced care provided by medical and paramedical professionals, psychological support, and resource teams received by VV-ECMO patients during their hospital stay (i.e., nutrition, wound care, physical therapy) should also be considered when comparing HRQoL [40]. On the other hand, given the non-interventional nature of the study, patient selection bias may have occurred, as shown by the reduced number of comorbidities in ECMO patients [40].

Hodgson et al. [41] reported that 52% of the VV-ECMO survivors had returned to work eight months after hospital discharge, and 26% managed to return to their previous working levels. Other studies showed higher return-to-work rates ranged between 67 and 71% at least a year post-hospital discharge [39, 42, 46]. Interestingly, despite longer support times, patients receiving active and passive physiotherapy in awake VV-ECMO [39], showed a similar return-to-work rate as the patients with shorter support times [42, 46]. Meanwhile, the results from Sylvestre et al. [45] showed that although their follow-up was longer (2 years after discharge), their observed return to work rate was considerably lower (46%) than the study by Hodgson et al. (52%) [41] and Wang et al. (67%) [46]. They argued that their patient cohort was older than the patients in the studies by Hodgson et al. [41] and Wang et al. [46].

Galazzi et al. reported that early rehabilitation should be strived for ICU patients, especially for ECMO patients [40], to minimize ICU-related weakness and fatigue [53]. Therefore, despite the more extended ICU stay, an acceptable degree of autonomy was achieved post-treatment in their study in an effort to improve general outcomes [39]. Additionally, the follow-up was performed in a later phase than in the study conducted by Wang et al. [46] (17 vs. 12.7 months), and patients, therefore, had more time to recover before follow-up took place. According to Schmidt et al. [24], a longer follow-up significantly improved SF-36 scores in role physical and role emotional domains in VV-ECMO survivors. Notably, ARDS survivors discharged from the ICU following conventional treatment showed to have a lower (50%) return-to-work rate compared to VV-ECMO survivors (67%)[46].

In several studies, the prevalence of physical impairment in VV-ECMO survivors was higher than the prevalence of mental impairment at various follow-up points between 12 months and 3 years after discharge [42, 44, 46]. Although the factors contributing to long-term physical impairment remain unclear, a ubiquitous ICU-acquired weakness and potential ECMO-specific sequelae may play a significant role [54, 55]. Reduced mobility, pain, or discomfort in the legs or feet was reported as VV-ECMO survivors’ main issues contributing to physical impairment [40, 41]. This can be explained by the fact that prolonged cannulation of the femoral veins can trigger localized nerve ischemia resulting in paraesthesia and limited mobility of the lower limbs [55].

It is well known that ICU survivors treated for ARDS, exposed to life-threatening circumstances, are prone to suffer from PTSD [47, 56]. This is confirmed by several previous studies that reported that a majority of ARDS survivors treated with VV-ECMO or conventional ventilatory support are suffering from anxiety and depression or PTSD [39, 43, 44, 57]. Both groups showed decreased HRQoL, especially on the role physical in VV-ECMO and emotional domain in conventionally treated survivors [40, 46]. However, survivors treated conventionally displayed a higher risk of PTSD [40, 43, 45, 47]. Additionally, these survivors appeared to have more limitations regarding physical activities, such as fatigue, weakness, restricted daily activities, and psychological issues interfering with their former way of life due to PTSD [40]. These observations have led the way for other investigators to evaluate neurocognitive dysfunction and its risk factors in ARDS patients supported by ECMO [45]. One challenge for studies considering long-term outcomes is knowing the baseline HRQoL status of the patients admitted due to ARDS. Thus, the extent to which the HRQoL deficits manifested due to ARDS is not always clear. Moreover, the deficits may be a function of prolonged and severe critical illness rather than specifically from ARDS or ECMO.

The present systematic review describes a reduced HRQoL in ARDS survivors supported by VV-ECMO and suggests this reduction to be similar to observations in conventionally treated ARDS survivors. Based on the quantitative design of the included studies and to gain further insight into the quality of life of VV-ECMO survivors, additional qualitative studies are warranted.